The cerebral nerve tissue represented by the cerebral cortex is made up of neurons governing sensory and perceptive functions and glia cells (astrocytes, oligodendrocytes and microglia) supporting the neurons, with the glia cells accounting for 90 percent of the whole tissue.
It was generally thought once that the central nervous system (CNS) is a static entity, and the immune system in this area is in a special environment (the so-called immune privilege). However, recent advances in molecular biological analysis have revealed that a variety of cytol,ines are produced and secreted intracerebrally and that the cellular or humoral immune system plays a pivotal role in the maintenance of homeostasis in the brain. At the same time, it has been suggested that excessive or abnormal activation of the immune system in CNS leads to the onset, progression and aggravation of various CNS diseases in the similar way as peripheral immune diseases.
Meanwhile, Alzheimer's disease (AD) is gathering increased attention these days as a type of dementia accompanied by degeneration and loss of neurons which is primarily found in persons of advanced age. With the increasing population of AD patients, the research and development work on drugs for the prevention and treatment of this disease is energetically pursued but the drugs so far developed are still providing only symptomatic relief at most and no fundamental drug therapy has been developed as yet.
In the intracerebral tissues of patients with Alzheimer's disease, accumulation of senile plaques and neurofibrillary tangles (NFT) are found and mentioned as a cause for the onset and progression of AD. Since deposits of .beta.-amyloid protein (.beta.-AP) are observed in senile plaques, it is clear that the .beta.-AP deposition, followed by aggregation and formation of senile plaques is a chief etiologic factor in Alzheimer's diseases. Moreover, the finding of accumulation of microglial cells in activated state around senile plaques has led to the theory that the aggregation gains momentum as microglial cells attempt to phagocytize and eliminate .beta.-AP and other deposits as foreign bodies and the formation of senile plaques is encouraged as a consequence. In senile plaques, complement deposits have also been found, and activation of the immune system has been pointed out as a cause for progression of AD morbidity and accompanying neuronal degeneration and loss. As it has thus been found that AD shares much with peripheral autoimmune diseases, it came to be regarded as an autoimmune disease of the brain. P. L. McGeer and co-workers, who paid attention to the epidemiologically low incidence of AD in patients with rheumatoid arthritis who received long-term anti-inflammatory drug therapy with an anti-inflammatory agent (indomethacin), and reported that the progression of AD could be supressed (WO 93/24115). Moreover, WO 93/08819 describes that lycoportine, an endogenous IL-1 antagonist, is useful for neurodegenerative diseases. However, since lycoportine is a macromolecular protein, the present inventors believe that it does not exhibit satisfactory stability or the absorption and transfer to the brain after oral administration.
Development of a novel compound having an excellent anti-neurodegenerative activity and being useful for the prophylaxis and therapy of encephalopathies has been ardently demanded.
U.S. Pat. No. 5,272,180, JP-A-1 104033 and JP-A-1 110624 describe quinone hydroxamic acid derivatives represented by the general formula: ##STR3## wherein R.sup.1 and R.sup.2 independently represent methyl group or methoxy group, or R.sup.1 and R.sup.2 are combined with each other to represent --CH.dbd.CH--CH.dbd.CH--; R.sup.3 represents an optionally substituted aromatic group or heterocyclic group; and
n denotes an integer of 2 to 8 (JP-A-1 110624), PA1 n denotes an integer of 5 or 6 (JP-A-1 104033), and their cell proliferation-inhibitory, neovascularization-inhibitory and autoimmune disease-ameliorating actions. PA1 wherein n denotes an integer of 1 to 7 and, Bulletin de la Societe Chimique France, pp.1314-1317 (1964) discloses production of the compound of the formula: EQU (C.sub.6 H.sub.5).sub.2 C(CN)--CH.sub.2 CH.sub.2 CH.dbd.CH--COOH. PA1 Q represents an optionally substituted divalent aliphatic hydrocarbon group optionally containing oxygen atom or sulfur atom; PA1 R.sup.1 represents hydrogen, an acyl group or an optionally substituted hydrocarbon group; PA1 X represents i) an electron-withdrawing group, ii) an optionally substituted aromatic group, iii) a group of the formula: ##STR7## wherein R.sup.2 and R.sup.3 independently represent hydrogen, an acyl group or an optionally substituted hydrocarbon group, or R.sup.2 and R.sup.3, taken together with the adjacent nitrogen atom, may form an N-containing heterocyclic ring, iv) an optionally substituted hydroxy group or v) an optionally substituted mercapto group, or a salt thereof (hereinafter referred to as compound (I)), and discovered through a series of pharmaceutical and pharmacological experiments, that since these compounds have, based on this specific chemical structure, unexpectedly exhibit excellent anti-neurodegenerative activity and are of low toxicity, and will show therapeutic and prophylactic effects on encephalopathies. PA1 (1) Compound (I); PA1 (2) the compound of above (1) wherein Q is a divalent aliphatic hydrocarbon group optionally containing oxygen atom or sulfur atom, and X is an electron-withdrawing group, an optionally substituted aromatic group or a group of the formula: ##STR8## (3) the compound of above (1) wherein Ar.sup.1 and Ar.sup.2 are independently i) a C.sub.6-14 aryl, ii) a 5- to 10-membered heteroaromatic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur or iii) a quinone group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano, optionally halogenated C.sub.1-6 alkyl, optionally halogenated C.sub.3-6 cycloalkyl, optionally halogenated C.sub.1-6 alkoxy, optionally halogenated C.sub.1-6 alkylthio, hydroxyl, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkylcarbonyl, carboxyl, C.sub.1-6 alkoxycarbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, C.sub.6-10 arylcarbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy, mono-C.sub.1-6 alkylcarbamoyloxy and C.sub.1-6 alkylcarboxamido, PA1 (4) the compound of above (3) wherein the aromatic groups for Ar.sup.1 and Ar.sup.2 are independently phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, thienyl or thiazolyl; PA1 (5) the compound of above (3) wherein Q is C.sub.2-8 alkylene group; PA1 (6) the compound of above (3) wherein R.sup.1 is hydrogen or an acyl group represented by the formula: --CO--R.sup.4, --CONH--R.sup.4, --CO--O--R.sup.4, --CS--NH--R.sup.4 or --CS--O--R.sup.4 wherein R.sup.4 is as defined in above; PA1 (7) the compound of above (3) wherein X is an electron-withdrawing group; PA1 (8) the compound of above (3) wherein X is a cyano group or an acyl group represented by the formula: --CO--R.sup.4, --CONH--R.sup.4, --CO--O--R.sup.4, --CS--NH--R.sup.4, --CS--O--R.sup.4, --SO.sub.2 --R.sup.4a or --SO--R.sup.4a wherein R.sup.4 and R.sup.4a are as defined above; PA1 (9) the compound of above (3) wherein Ar.sup.1 and Ar2 are independently a phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 2-benzothiazolyl, 2-thienyl, 2-thiazolyl or 1-isoquinolyl group, each of which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen and an optionally halogenated C.sub.1-6 alkoxy, PA1 (10) the compound of above (1) wherein Ar.sup.1 and Ar.sup.2 are independently a phenyl, 2-naphtyl, 2-pyridyl, 2-benzothiazolyl, 2-quinolyl, 2-thienyl or 2-thiazolyl group, each of which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen, optionally halogenated C.sub.1-3 alkyl, optionally halogenated C.sub.1-3 alkoxy, hydroxyl and mono-C.sub.1-6 alkylcarbamoyloxy, PA1 (11) the compound of above (1) which is PA1 (12) a process for producing a compound (I), which comprises reacting a compound of the formula: ##STR10## wherein all symbols are as defined above or a salt thereof or a reactive derivative thereof at the carboxyl group with hydroxylamine, and if necessary, allowing the resultant compound to react with a compound of the formula: EQU Y--R.sup.1a PA1 wherein Y represents a leaving group and R.sup.la represents an acyl group or an optionally substituted hydrocarbon group or a salt thereof; PA1 (13) a pharmaceutical composition which comprises the compound (I), if necessary together with a pharmaceutically acceptable carrier; PA1 (14) the composition of above (13) which is an anti-neurodegenerative composition; PA1 (15) the composition of above (13) which is for preventing or treating neurodegenerative diseases; PA1 (16) the composition of above (15) which is for preventing or treating Alzheimer's disease or multiple sclerosis, and so forth. PA1 (i) C.sub.2-8 alkylene groups (e.g. --CH.sub.2, --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.6 --, --(CH.sub.2).sub.7 --, --(CH.sub.2).sub.8 --, etc.) PA1 (ii) C.sub.2-8 alkenylene groups (e.g. --CH.sub.2 --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH--CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH=CH--, --CH.dbd.CH--CH.sub.2 --CH.sub.2 --CH.sub.2 -- and --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.dbd.CH--, etc.) PA1 (iii) alkynylene groups (e.g. --C.tbd.C--, --CH.sub.2 --C.tbd.C--, --CH.sub.2 --C.tbd.C--CH.sub.2 --CH.sub.2 -, etc.) PA1 (iv) a group of the formula: --(CH.sub.2).sub.n --M--(CH.sub.2).sub.m -- wherein M represents O, S, SO or SO.sub.2, n and m independently represent an integer of 0 to 8 (preferably 1 to 4), and n+m represents an integer of 2 to 8. PA1 a) C.sub.1-6 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl), PA1 b) C.sub.2-6 alkenyl groups (e.g. vinyl, allyl, isopropenyl; butenyl, isobutenyl and sec-butenyl), PA1 c) C.sub.2-6 alkynyl groups (e.g. propargyl, ethynyl, butynyl and 1-hexynyl), PA1 d) C.sub.3-6 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl optionally condensed with benzene ring optionally having one to three C.sub.1-6 alkoxy groups (e.g. methoxy)), PA1 e) C.sub.6-14 aryl groups (e.g. phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-indenyl and 2-anthryl), preferably phenyl group, PA1 f) C.sub.7-16 aralkyl groups (e.g. benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentyl), preferably benzyl group. PA1 Q is a C.sub.2-8 alkylene group, PA1 R.sup.1 is hydrogen or an acyl group, and PA1 X is an electron-withdrawing group. PA1 Ar.sup.1 and Ar.sup.2 are independently a phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinoly, 5-quinolyl, 8-quinolyl, 2-benzothiazolyl, 2-thienyl, 2-thiazolyl or 1-isoquinolyl group, each of which may be substituted by halogen atom or an optionally halogenated C.sub.1-6 alkoxy group, PA1 Q is a straight C.sub.4-6 alkylene group, PA1 R.sup.1 is hydrogen atom or an acyl group represented by the formula: --CO--R.sup.4 or --CONH--R.sup.4, PA1 R.sup.4 is (i) a C.sub.1-6 alkyl group, (ii) a C.sub.6-14 aryl group or (iii) a mono-cyclic N-containing aromatic group, each of which may be substituted by halogen, optionally halogenated C.sub.1-6 alkyl groups or optionally halogenated C.sub.1-6 alkoxy groups, and PA1 X is cyano group. PA1 wherein Ar.sup.3 represents an optionally substituted aromatic group and X is of the same meaning as defined above, in the presence of a base to provide the compound (III).
U.S. Pat. No. 5,180,742 and JP-A-61 44840 disclosed that a compound represented by the general formula: ##STR4## wherein R.sup.1, R.sup.2 and R.sup.3 each represents e.g. hydrogen atom or methyl group; R.sup.4 represents an optionally substituted aliphatic group, aromatic group or heterocyclic group; R.sup.5 represents e.g. an optionally esterified or amidated carboxylic group; Z represents. e.g. --CH.dbd.CH--; n denotes an integer of 0 to 10; m denotes an integer of 0 to 3; and k denotes an integer of 0 to 5, has 5-lipoxygenase inhibitory activity and is of value as an antiasthmatic, antiallergic or cerebral circulation ameliorating agent.
Furthermore, Bulletin de la Societe Chimique France, pp.1345-1350 (1956) discloses production of compounds of the formula: EQU (C.sub.6 H.sub.5).sub.2 C(CN)--(CH.sub.2).sub.n --COOH and (C.sub.6 H.sub.5).sub.2 C(CN)--(CH.sub.2).sub.n+1 --CO--OC.sub.2 H.sub.5
However, these literature references do not discuss any medicinal effects of these compounds.